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1 Department of Pharmaceutics, University of Washington, Seattle, WA, USA
2 Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
* To whom correspondence should be addressed. E-mail: jash{at}u.washington.edu.
Placental efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) protect the developing fetus from exposure to potentially toxic xenobiotics. However, little is known about the expression of these transporters in human placentae of different gestational ages. Therefore, we quantified the expression of P-gp and BCRP in human placentae of different gestational ages. We also measured the expression of various nuclear regulatory factors such as the pregnane xenobiotic factor (PXR) to determine if their expression also changes with gestational age. Syncitial microvillous plasma membranes were isolated from human placentae of various gestational ages (60-90 days, 90-120 days, and full-term C-section placentae). P-gp and BCRP expression (protein) in these preparations were measured by Western blot analysis followed by an ELISA. Expression (mRNA) of P-gp, BCRP and nuclear regulatory factors in the placentae were quantified by quantitative real-time PCR. P-gp expression (relative to that of alkaline phosphatase) was significantly (p<0.05) higher (44.8-fold as protein; 6.5-fold as mRNA) in early gestational age human placentae (60-90 days) versus term placentae. In contrast, BCRP (protein and mRNA) and nuclear regulatory factors (mRNA) expression in placental tissue did not change significantly with gestational age. However, placental expression of P-gp and hCG-
transcripts was highly correlated (r=0.73; p<0.0001; Spearman rank correlation). Expression of P-gp, but not BCRP, decreases dramatically with gestational age in human placentae. This decrease in P-gp expression is not caused by a change in expression of nuclear receptor transcripts but appears to be related to hCG- expression. The placental P-gp expression appears to be upregulated in early pregnancy to protect the fetus from xenobiotic toxicity at a time when it is most vulnerable to such toxicity.
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